Immediate-early genes, such as c-fos, are induced in the brain by cocaine and other psychotropic drugs. This induction is thought to be mediated via the activation of dopamine D1 and glutamate N-methyl-D-aspartate (NMDA) receptor subtypes. Because alcohol selectively blocks NMDA receptor function, we determined the ability of alcohol to block the expression of c-fos normally induced by systemic cocaine exposure in perikarya of the rat striatum. Acute administration of alcohol (2 g/kg; IP) approximately 30 min prior to a single cocaine (20 mg/kg) injection significantly reduced the patchy appearance of intensely immunoreactive gene signal in dorsal-central quadrants of the caudate putamen. Separate administration of three doses of alcohol alone (1, 2, or 3 g/kg) was ineffectual in inducing FOS-like protein in this or other regions of the rat brain. The blockade of the encoded protein by alcohol was partial in magnitude reminiscent of that produced by MK-801 and related NMDA receptor antagonist drugs. Furthermore, the blockade of cocaine-induced FOS-like protein by alcohol occurred at a dose which produced a blood alcohol concentration of approximately 180 mg/dl (40 mM), comparable to that detected in intoxicating humans. Considering the fact that the concomitant use of alcohol and cocaine is the most common substance abuse pattern found in the addictive population, the present results suggest an antagonist effect exerted by these two drugs at the transcriptional level and further support the consensus that NMDA receptors are the plausible surface-target elements mediating some of the effects of alcohol and cocaine.